Effects of Atorvastatin on T-Cell Activation and Apoptosis in Systemic Lupus Erythematosus and Novel Simulated Interactions With C-Reactive Protein and Interleukin 6

Jitong Sun; Pritam Kumar Panda; Shailesh Kumar Samal; Rajeev Ahuja; Sofia Ajeganova; Ingiäld Hafström; Anquan Liu; Johan Frostegård

doi:10.1002/acr2.11305

Effects of Atorvastatin on T-Cell Activation and Apoptosis in Systemic Lupus Erythematosus and Novel Simulated Interactions With C-Reactive Protein and Interleukin 6

ACR Open Rheumatol. 2021 Sep;3(9):642-653. doi: 10.1002/acr2.11305. Epub 2021 Jul 23.

Authors

Jitong Sun¹, Pritam Kumar Panda², Shailesh Kumar Samal¹, Rajeev Ahuja³, Sofia Ajeganova⁴, Ingiäld Hafström⁵, Anquan Liu¹, Johan Frostegård¹

Affiliations

¹ Karolinska Institutet, Stockholm, Sweden.
² Uppsala University, Uppsala, Sweden.
³ Uppsala University and Royal Institute of Technology, Stockholm, Sweden.
⁴ Karolinska Institutet, Stockholm, Sweden, and Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
⁵ Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.

Abstract

Objective: We study activation of T helper 17 (Th17) and regulatory T (Treg) cells and induction of apoptosis in cells from patients with systemic lupus erythematosus (SLE) compared with controls and effects of atorvastatin and its simulated interactions with other compounds.

Methods: Mononuclear cells from 10 patients with SLE and 10 controls were cultured in conditions that induce Th17 and/or Treg cell polarization and/or apoptosis and were studied by FACScan. Gene expression was determined by quantitative real-time reverse transcription-polymerase chain reaction. Cytokines in plasma were determined by enzyme-linked immunosorbent assay. The Search Tool for Interactions of Chemicals (STITCH) was used to retrieve information regarding the binding properties of atorvastatin.

Results: Among patients with SLE, the proportion of Th17 (CD4⁺ IL17⁺ ) cells was higher compared with controls after activation, with Th17 or Treg polarizing cytokines, phorbol myristate acetate, and ionomycin. In contrast, Treg cells (CD4⁺ CD25⁺ CD127^dim/- ) frequencies were lower. CD95 stimulation induced relatively more apoptosis in Treg cells and less in Th17 cells, as compared with controls. Addition of atorvastatin normalized Th17/Treg cell balance and apoptosis induction. Accordingly, the ratio of RORC/FoxP3 decreased in patients with SLE. Interleukin 17 and interleukin 6 (IL-6) levels were increased in patients with SLE. Atorvastatin interacted strongly with C-reactive protein (CRP) and also significantly with IL-6.

Conclusion: There is a higher proportion of Th17 cells and a lower proportion of Treg cells in patients with SLE after activation. Th17 cells were more resistant than Treg cells to CD95-induced apoptosis in SLE. Atorvastatin normalized these effects. Our findings reveal a novel mechanism behind the imbalance of Th17/Treg cells with implications for treatment in SLE. We determine for the first time simulated interaction between atorvastatin, CRP, and IL-6, implying a novel role of atorvastatin.

Abstract

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